The present invention, in some embodiments thereof, relates to a method of treating diseases for which inhibiting a proteasome is advantageous by using agents, which specifically target the 19S proteasomal complex.
Proteasomal protein degradation is crucial in maintaining cellular integrity and in regulating key cellular processes including cell cycle, proliferation and cell death. Proteasomal degradation is mediated mainly by two proteasomal complexes; the 26S proteasome, that consists of the 20S catalytic domain and two 19S regulatory particles (RP) and the 20S proteasome in isolation (1, 2). In the well-characterized ubiquitin-proteasome system (UPS) a protein is targeted for degradation by specific modification by a set of enzymes that conjugates a poly-ubiquitin chain to the protein. The poly-ubiquitinated substrate is then recognized by specific subunits of the 19S RP of the 26S proteasome where it is de-ubiquitinated, unfolded by the ATPases and translocated into the 20S catalytic chamber for degradation. Recently a ubiquitin-independent proteasomal degradation pathway has been described whereby intrinsically disordered proteins (IDPs) such as p53, c-FOS, BimEL (8-10) and others can be degraded by the 20S proteasome in a process that does not involve active ubiquitin tagging. The 20S proteasome has been also shown to be activated by the REG (11S) family members inducing the degradation of SRC-3, p21 and other proteins. Thus, there are at least two distinct proteasomal protein degradation pathways each regulated by the distinct 26S and 20S proteasomal complexes.
The UPS as a regulator of cell death has been a tempting target for drug development for many pathologies specifically cancer (14-16). Various tumors have been shown to express high levels of proteasomal subunits and higher proteasomal activity (17-19). A number of studies suggests that cancer cells exhibit high sensitivity to proteasomal inhibition (20). Sensitivity to proteasomal inhibition was specifically shown efficient in lymphoid malignancies, particularly multiple myeloma where the proteasomal inhibitor Brotezamide (VELCADE, PS-341) was approved for therapy (21-23). Proteasome inhibitors were also shown efficient in various screens of solid and hematologic tumors (24, 25) and currently there is an increasing number of cancers that are in the process of clinical trials with different proteasomal inhibitors (26). Proteasomal inhibitors such as Brotezamide, MG132, and β-lapachone inhibit the 20S proteasome (27) therefore these drugs inhibit the entire proteasomal activity including the 26S (that is comprised of the 20S and 19S) and the 20S proteasomal complexes.
Hiroshi Y et al [Mol Cancer Ther 2006; 5(1):29-38] teaches that targeting the ATPase subunits of the 19S regulatory complex in the proteasome enhances spindle poison-mediated cell killing in cancer cells.
Other background art includes Byrne A. et al. ECR 2010; 316:258-271 and International Patent Application WO2009117196.